Long-Term Follow-Up of Newborns with 22q11 Deletion Syndrome and Low TRECs

• Published in: Journal of clinical immunology Vol. 42; no. 3; pp. 618 - 633
• Main Authors: Framme, Jenny Lingman, Lundqvist, Christina, Lundell, Anna-Carin, van Schouwenburg, Pauline A., Lemarquis, Andri L., Thörn, Karolina, Lindgren, Susanne, Gudmundsdottir, Judith, Lundberg, Vanja, Degerman, Sofie, Zetterström, Rolf H., Borte, Stephan, Hammarström, Lennart, Telemo, Esbjörn, Hultdin, Magnus, van der Burg, Mirjam, Fasth, Anders, Oskarsdóttir, Sólveig, Ekwall, Olov
• Format: Journal Article
• Language: English
• Published: New York Springer US 2022; Springer Nature B.V
• Subjects: 22q11 Deletion Syndrome; 22q11.2 deletion syndrome; Adolescent; Biomedical and Life Sciences; Biomedicine; Cell differentiation; Children; Cytotoxicity; DiGeorge syndrome; Discriminant analysis; DNA; Follow-Up Studies; Gene deletion; Helper cells; Humans; Immune response; Immunoglobulins; Immunologi inom det medicinska området; Immunological memory; Immunology; Immunology in the medical area; Immunoregulation; Infant, Newborn; Infants; Infectious Diseases; Internal Medicine; long-term outcome; Lymphocytes B; Lymphocytes T; Lymphopenia; Lymphopenia - diagnosis; Medical Microbiology; Medicin och hälsovetenskap; Memory cells; Neonatal Screening; Neonates; Newborn babies; newborn screening; Original; Original Article; Pediatrics; Pediatrik; Receptors, Antigen, T-Cell - genetics; Severe combined immunodeficiency; Severe Combined Immunodeficiency - diagnosis; T cell receptors; T lymphopenia; Telomeres; TREC; 22q11.2 deletion syndrome; DiGeorge syndrome; long-term outcome; T lymphopenia; TREC; severe combined immunodeficiency; newborn screening
• ISSN: 0271-9142; 1573-2592; 1573-2592
• DOI: 10.1007/s10875-021-01201-5

Background Population-based neonatal screening using T-cell receptor excision circles (TRECs) identifies infants with profound T lymphopenia, as seen in cases of severe combined immunodeficiency, and in a subgroup of infants with 22q11 deletion syndrome (22q11DS). Purpose To investigate the long-term prognostic value of low levels of TRECs in newborns with 22q11DS. Methods Subjects with 22q11DS and low TRECs at birth (22q11Low, N =10), matched subjects with 22q11DS and normal TRECs (22q11Normal, N= 10), and matched healthy controls (HC, N= 10) were identified. At follow-up (median age 16 years), clinical and immunological characterizations, covering lymphocyte subsets, immunoglobulins, TRECs, T-cell receptor repertoires, and relative telomere length (RTL) measurements were performed. Results At follow-up, the 22q11Low group had lower numbers of naïve T-helper cells, naïve T-regulatory cells, naïve cytotoxic T cells, and persistently lower TRECs compared to healthy controls. Receptor repertoires showed skewed V-gene usage for naïve T-helper cells, whereas for naïve cytotoxic T cells, shorter RTL and a trend towards higher clonality were found. Multivariate discriminant analysis revealed a clear distinction between the three groups and a skewing towards Th17 differentiation of T-helper cells, particularly in the 22q11Low individuals. Perturbations of B-cell subsets were found in both the 22q11Low and 22q11Normal group compared to the HC group, with larger proportions of naïve B cells and lower levels of memory B cells, including switched memory B cells. Conclusions This long-term follow-up study shows that 22q11Low individuals have persistent immunologic aberrations and increased risk for immune dysregulation, indicating the necessity of lifelong monitoring. Clinical Implications This study elucidates the natural history of childhood immune function in newborns with 22q11DS and low TRECs, which may facilitate the development of programs for long-term monitoring and therapeutic choices.